Throughout this application, various references are referred to. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Various procedures for treating Parkinson""s Disease have been established and many of them are currently in widespread use. European Patent No. 436492B provides a detailed discussion of treatments available and summarizes many of their drawbacks. There remains a need for a drug therapy that provides a prolonged and sustained amelioration of the symptoms associated with Parkinson""s Disease.
A variety of substituted 1-aminoindans have been proposed to have some activity in the central nervous system (CNS). This group of compounds have a wide range of activities, for example, U.S. Pat. No. 4,096,173 discloses 1-aminoindans with ring chloro substituents as having anti-allergic, anti-spasmodic and local anesthetic activities, whereas U.S. Pat. No. 3,886,168 discloses the anti-inflammatory and vasodilatory activity of certain 1-aminomethylindans. It is hypothesized therein that the activity may be based in the CNS though no evidence is provided or suggested to support the hypothesis. British Patent No. 852,735 discloses 1-aminoindans with a lower alkoxy group in the 5 position as being active in dilating coronary blood vessels.
U.S. Pat. No. 3,637,740 discloses 4-alkoxy-5-chloro-1-aminoindans as anti-depressants or anti-anxiety agents, although no clear evidence is provided of either activity.
Horn et al. (J. Pharm. Exp. Ther. 1972 180(3) 523) have shown that 2-aminoindan is a far superior inhibitor of catecholamine uptake than 1-aminoindan and therefore dismissed the latter as a candidate for use in the treatment of Parkinson""s Disease. Martin et al. (J. Med. Chem. 1973 16(2) 147 and J. Med. Chem 1974 17(4) 409) describe experiments wherein N-methyl-5-methoxy derivatives of 1-aminoindan are investigated as having monoamine oxidase (MAO) inhibitory activity.
Oshiro et al. (J. Med. Chem. 1991 34 2004-2013) disclose a wide range of 7-hydroxy-1-aminoindan derivatives that they subjected to screening for use as a cerebroprotective agent using an antihypoxic test and as a CNS stimulatory agent using a cerebral trauma test. In the resultant structure-activity-analysis undertaken it was found that replacement of the 7-hydroxy group by a methoxy group resulted in loss of activity in the antihypoxic test but not in the cerebral trauma test. Their conclusion was that the 7-hydroxy group is essential to obtain the desired activity. This is evident from their subsequent paper wherein a broader range of 7-hydroxy derivatives are screened (J.Med.Chem 1991 34 2014-2020). These 7-hydroxy-1-aminoindans are defined in U.S. Pat. Nos. 4,788,130, 4,792,628, 4,895,847, 5,055,474 and 5,242,919 all assigned to Otsuka Pharmaceutical Co. Japan. It has surprisingly been found that a range of substituted and unsubstituted 1-aminoindans have activity in suppressing the symptoms emanating from the dopaminergic hypofunction that is associated with Parkinson""s Disease; in improving cognition in dementias such as senile dementia, Parkinson-type dementia and dementia of the Alzheimer""s type; in providing protection against epilepsy, convulsions, seizures; and in improving post-head trauma motor function, and reducing trauma-induced cerebral oedema.
The present invention also relates to a process for the synthesis of optically active aminoindan derivatives that have been described as possessing utility in the treatment of Parkinson""s Disease, dementia, epilepsy, convulsions or seizures.
Several methods of preparing optically active derivatives of 1-aminoindan have been described in the art which include, for example, the method of Lawson and Rao, Biochemistry, 19, 2133 (1980), methods in references cited therein, and the method of European patent No. 235, 590.
Optically active compounds containing an amine group attached to a chiral carbon atom may be prepared by the resolution of a racemic mixture of the R and S enantiomers. Such a resolution can be accomplished by resolution methods well known to a person skilled in the art, such as the formation of diastereomeric salts with chiral acids, or those described in U.S. Pat. No. 4,833,273, issued May 23, 1989 (Goel) and those listed in J. Jacques, A. Collet and S. Wilen, xe2x80x9cEnantiomers, Racemates and Resolutionsxe2x80x9d Wiley, New York (1981) such as tartaric, malic, mandelic acid, or N-acetyl derivatives of amino acids, such as N-acetyl leucine, followed by re-crystallization to isolate the diastereomeric salt of the desired enantiomer.
Kipping and Hall, J. Chem. Soc. (1901) 79 430, succeeded in the formation of diastereomeric alpha-bromocamphor-sulphonic acid salts of the compound N-benzyl-1-aminoindan. Isolation of the individual enantiomers by the addition of barium hydroxide failed and the racemate was obtained.
The preparation of the S enantiomer of the benzoate salt of N-benzyl-1-aminoindan from (S)-1-aminoindan has been described by Takaneda S et al. JCS Perkin II (1978) 95-99.
It is an object of this invention to provide an economical, commercially useful method for preparing optically active enantiomers of 1-aminoindan and derivatives thereof.
It has been surprisingly observed that by using a particular resolving agent on a particular class of 1-aminoindan derivative, a resolution is effected that produces high yields of optically active enantiomer.
This invention provides a method for treating Parkinson""s disease, dementia, epilepsy, convulsions, or seizures in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula: 
or a pharmaceutically acceptable salt thereof; wherein n is 0, 1 or 2; R1 and R2 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, nitro, NHxe2x80x94R3, C(O)xe2x80x94R3, or C(O)xe2x80x94NR9R10; R3 is hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-4 alkoxy, or substituted or unsubstituted C6-12 aryl; and R4 and R5 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, xe2x80x94C(O)xe2x80x94R6, xe2x80x94Yxe2x80x94C(O)xe2x80x94R7, or Yxe2x80x94(SO2)NR9R10; wherein R6 is hydrogen, hydroxy, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or Axe2x80x94NR9R10, wherein A is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, and R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or indanyl; Y is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted C7-C12 aralkyl, and R7 is hydrogen, hydroxy, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl or NR9R10, wherein R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or indanyl.
This invention provides a method for treating epilepsy, convulsions, or seizures in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula: 
or a pharmaceutically acceptable salt thereof; wherein n is 0, 1 or 2; R1 and R2 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, nitro, NHxe2x80x94R3, C(O)xe2x80x94R3, or C(O)xe2x80x94NR9R10; R3 is hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-4 alkoxy, or substituted or unsubstituted C6-12 aryl; and R4 and R5 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, alkynyl, xe2x80x94C(O)xe2x80x94R6, xe2x80x94Yxe2x80x94C(O)xe2x80x94R7, or Yxe2x80x94(SO2)NR9R10; wherein R6 is hydrogen, hydroxy, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or Axe2x80x94NR9R10, wherein A is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, and R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or indanyl; Y is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted C7-C12 aralkyl, and R7 is hydrogen, hydroxy, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl or NR9R10, wherein R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or indanyl.
This invention provides a compound selected from the group consisting of 7-methyl-1-aminoindan, 5-methyl-1-aminoindan, (R)-6-hydroxy-1-aminoindan, 3,5,7-trimethyl-1-aminoindan, 4,5-dimethoxy-1-aminoindan, (R)-4,5-dimethoxy-1-aminoindan, (S)-4,5-dimethoxy-1-aminoindan, 4-hydroxy-5-methoxy-1-aminoindan, 6-hydroxy-5-methoxy-1-aminoindan, N-(4-aminobutanoyl)-1-aminoindan. (R)-N-formyl-1-aminoindan, (S)-N-formyl-1-aminoindan, (R)-N-acetyl-1-aminoindan, N-acetyl-7-methyl-1-aminoindan, N-acetyl-6-fluoro-1-aminoindan, (R)-N-acetyl-6-fluoro-1-aminoindan, (S)-6-Methoxy-1-aminoindan, N-acetyl-6-methoxy-1-aminoindan, (R)-N-acetyl-4,5-dimethoxy-1-aminoindan, N-(2-acetamido)-1-aminoindan, (R)-N-(2-acetamido)-1-aminoindan, (S)-N-(2-acetamido)-1-aminoindan, N-(2-acetamido)-6-fluoro-1-aminoindan, N-(3-cyanopropyl)-1-aminoindan, N-(2-acetamido)-1-aminotetralin, N-(2-N-Boc-aminoacetyl)-1-aminoindan, N-(2-Aminoacetyl)-1-aminoindan, N-Benzoyl-1-aminoindan, N-(2-n-Propylpentanoyl)-1-aminoindan, N-methyl-N-acetyl-1-aminoindan, (R)-N-methyl-N-acetyl-1-aminoindan, N-(2-propionamido)-1-aminoindan, N-(2-phenylacetyl)-1-aminoindan, N-(m-anisoyl)-1-aminoindan, N-(4xe2x80x2-fluorobenzoyl)-1-aminoindan, N-(p-4-toluoyl)-1-aminoindan, (S)-(1-indanyl)-glycine, N,N-di-(2-acetamido)-1-aminoindan, N-(1-indanyl)-aminoacetonitrile 6-cyano-N-acetyl-1-aminoindan, 6-carboxamido-N-acetyl-1-aminoindan, 6-ethoxycarbonyl-N-acetyl-1-aminoindan, 2-(1-indanamino)-N-isopropylethanesulfonamide, 2-(1-indanamino)-N-(1-indanyl)ethanesulfonamide, (R,R)-2-(1-indanamino)-N-(1-indanyl)ethanesulfonamide, N-(4-(di-n-propylsulfamoyl)benzoyl)-1-aminoindan, N,Nxe2x80x2-bis-(1-indanyl)adipamide, N,Nxe2x80x2-bis-(R)-(1-indanyl)adipamide, N,Nxe2x80x2-bis(R)-(1-indanyl)succinamide, trans-2-methyl-N-acetyl-1-aminoindan, cis-2-methyl-N-acetyl-1-aminoindan, and salts thereof.
The compounds of general formula 1 possess neuroprotective activity. Accordingly, this invention provides a method for treating acute neurological traumatic disorder or neurotrauma in a subject comprising administering to the subject a therapeutically effective amount of a compound of the formula: 
or a pharmaceutically acceptable salt thereof; wherein n is 0, 1 or 2; R1 and R2 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, halogen, nitro, NHxe2x80x94R3, C(O)xe2x80x94R3, or C(O)xe2x80x94NR9R10; R3 is hydrogen, substituted or unsubstituted C1-C4 alkyl, hydroxy, substituted or unsubstituted C1-4 alkoxy, or substituted or unsubstituted C6-12 aryl; and R4 and R5 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, xe2x80x94C(O)xe2x80x94R6, xe2x80x94Yxe2x80x94C(O)xe2x80x94R7, or Yxe2x80x94(SO2)NR9R10; wherein R6 is hydrogen, hydroxy, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or Axe2x80x94NR9R10, wherein A is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, and R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or indanyl; Y is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted C7-C12 aralkyl, and R7 is hydrogen, hydroxy, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl or NR9R10, wherein R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, or indanyl.
This invention provides a method for preparing an optically active enantiomer of a compound of the formula: 
wherein the enantiomer is optically active at the C1 position; n is 0, 1 or 2; R1 and R2 are each independently hydrogen, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, or halogen; and R3 is hydrogen or unsubstituted C1-C4 alkyl; comprising incubating in a reaction mixture a racemic N-benzyl analog of the compound with an optically active enantiomer of mandelic acid; converting the optically active ammonium salt obtained to its corresponding optically active base; and reducing the base to the optically active enantiomer of the compound.
This invention provides a method for preparing racemic N-benzyl-1-aminoindan comprising reacting 1-chloroindane with benzylamine in an inert solvent.